Single-cell Landscape Analysis of the Circulating Human B Cell Pool under Selective Pressure of Allogeneic Stem Cell Transplantation

Abstract: After allogeneic hematopoietic stem cell transplantation (allo-HCT), donor-derived B cells develop under selective pressure from alloantigens and play a substantiated role in the autoimmune-like syndrome, chronic graft versus host disease (cGVHD). We performed single-cell RNA-Sequencing (scRNA-Seq) of blood B cells from allo-HCT patients and resolved 10 clusters that were distinguishable by signature genes for maturation, activation and memory. Notably, allo-HCT patient memory B cells displayed some striking transcriptional differences when compared to memory B cells from healthy individuals or non-HCT patients, suggesting molecular differences with a propensity for autoreactivity. To inform more specifically about transcriptional programs important for allo-HCT tolerance, we assessed all 10 clusters for differentially expressed genes (DEGs) between patients with Active cGVHD vs. those without disease (No cGVHD). Data reveal insight into DEGs that may influence multiple aspects of B cell function in allo-HCT, leading to chronic B cell activation in Active cGVHD and our observed expansion of potentially pathogenic atypical/age-related memory B cell (ABC) subsets within a B Cell Receptor (BCR)-experienced memory cluster. Data also indicate chronic B-cell activation and diversification in allo-HCT is potentially plastic, and may be manipulated therapeutically. Our findings have implications in understanding how alloreactivity may lead to human autoimmune disease, and identify potentially novel targets for future study and intervention.